Thrombus formation is normally the result of tissue injury which initiates the coagulation cascade and has the effect of slowing or preventing blood flow in wound healing. Other factors which are not directly related to tissue injury like atherosclerosis and inflammation may also initiate the coagulation cascade and may lead to pathological consequences.
Blood coagulation is a complex process involving a progressively amplified series of enzyme activation reactions in which plasma zymogens are sequentially activated by limited proteolysis. Mechanistically, the blood coagulation cascade has been divided into intrinsic and extrinsic pathways, which converge at the activation of factor X; subsequent generation of the thrombin proceeds through a single common pathway (see Scheme 1). ##STR1##
Present evidence suggests that the intrinsic pathway plays an important role in the maintenance and growth of fibrin formation, while the extrinsic pathway is critical in the initiation phase of blood coagulation (H. Cole, Aust. J. Med. Chem. 16 (1995) 87; G. J. Broze, Blood Coagulation and Fibrinolysis, Vol. 6, Suppl.1 (1995) S7-S13). It is generally accepted that blood coagulation is physically initiated upon formation of a tissue factor(TF)/factor VIIa complex. Once formed, this complex rapidly initiates coagulation by activating factors IX and X. The newly generated activated factor X, i.e., factor Xa, then forms a one-to-one complex with factor Va and phospholipids to form a prothrombinase complex, which is responsible for converting soluble fibrinogen to insoluble fibrin via the activation of thrombin from its precursor prothrombin. As time progresses, the activity of the factor VIIa/tissue factor complex (extrinsic pathway) is suppressed by a Kunitz-type protease inhibitor protein, TFPI, which, when complexed to factor Xa, can directly inhibit the proteolytic activity of factor VIIa/tissue factor. In order to maintain the coagulation process in the presence of an inhibited extrinsic system, additional factor Xa is produced via the thrombin-mediated activity of the intrinsic pathway. Thus, thrombin plays a dual autocatalytic role, mediating its own production and the conversion of fibrinogen to fibrin.
The autocatalytic nature of thrombin generation is an important safeguard against uncontrolled bleeding and it ensures that, once a given threshold level of prothrombinase is present, blood coagulation will proceed to completion. The ability to form blood clots is vital to survival. In certain disease states, however, the formation of blood clots within the circulatory system is itself a source of morbidity. It is nevertheless not desirable in such disease states to completely inhibit the clotting system because life threatening hemorrhage would ensue. Thus, it is most desirable to develop agents that inhibit coagulation by inhibition of factor VIIa without directly inhibiting thrombin.
In many clinical applications, there is a great need for the prevention of intravascular blood clots or for some anticoagulant treatment. The currently available drugs are not satisfactory in many specific clinical applications. For example, nearly 50% of patients who have undergone a total hip replacement develop deep vein thrombosis "DVT". The currently approved therapies are fixed dose low molecular weight heparin "LMWH" and variable dose heparin. Even with these drug regimes 10% to 20% of patients develop DVT and 5% to 10% develop bleeding complications.
Another clinical situation for which better anticoagulants are needed concerns subjects undergoing transluminal coronary angioplasty and subjects at risk for myocardial infarction or suffering from crescendo angina. The present, conventionally accepted therapy, which consists of administering heparin and aspirin, is associated with a 6% to 8% abrupt vessel closure rate within 24 hours of the procedure. The rate of bleeding complications requiring transfusion therapy due to the use of heparin also is approximately 7%. Moreover, even though delayed closures are significant, administration of heparin after termination of the procedures is of little value and can be detrimental.
The most widely used blood-clotting inhibitors are heparin and the related sulfated polysaccharides, LMWH, and heparin sulfate. These molecules exert their anti-clotting effects by promoting the binding of a natural regulator of the clotting process, anti-thrombin III, to thrombin and to factor Xa. The inhibitory activity of heparin primarily is directed toward thrombin, which is inactivated approximately 100 times faster than factor Xa. Hirudin and hirulog are two additional thrombin-specific anticoagulants presently in clinical trials. However, these anticoagulants, which inhibit thrombin, also are associated with bleeding complications. Preclinical studies in baboons and dogs have shown that targeting enzymes involved at earlier stages of the coagulation cascade, such as factor Xa or factor VIIa, prevents clot formation without producing the bleeding side effects observed with direct thrombin inhibitors. T. Yokoyama, A. B. Kelly, U. M. Marzec, S. R. Hanson, S. Kunitada, L. A. Harker, Circulation 92 (1995) 485-491; L. A Harker, S. R. Hanson, A. B. Kelly, Thromb. Hemostas. 74 (1995) 464-472; C. R. Benedict, J. Ryan, J. Todd, K. Kuwabara, P. Tyburg, Jr., J. Cartwright, D. Stern, Blood 81 (1993) 2059-2066.
Specific inhibition of the factor VIIa/TF catalytic complex using monoclonal antibody (International Patent Application No. WO92/06711) and a protein such as chloromethyl ketone inactivated FVIIa (International Patent Application No. WO96/12800 and WO97/47651) is an extremely effective means of controlling thrombus formation caused by acute arterial injury or the thrombotic complications related to bacterial septicemia. There is also experimental evidence suggesting that inhibition of factor VIIa/TF activity inhibits restenosis following ballon angioplasty. L. A. Harker, S. R. Hanson, J. N. Wilcox, A. B. Kelly, Haemostasis 26 (1996) S1:76-82. Bleeding studies have been conducted in baboons and indicate that inhibition of the factor VIIa/TF complex has the widest safety window with respect to therapeutic effectiveness and bleeding risk of any anticoagulant approach tested including thrombin, platelet and factor Xa inhibition. L. A. Harker, S. R. Hanson, A. B. Kelly, Thromb. Hemostas. 74 (1995) 464-472.
A specific inhibitor of factor VIIa would have substantial practical value in the practice of medicine. In particular, a factor VIIa inhibitor would be effective under circumstances where the present drugs of choice, heparin and related sulfated polysaccharides, are ineffective or only marginally effective. Thus, there exists a need for a low molecular weight, factor VIIa-specific blood clotting inhibitor that is effective, but does not cause unwanted side effects. The present invention satisfies this need by providing factor VIIa activity inhibiting derivatives of formula I and by providing related advantages as well.
The compounds of formula I are inhibitors of the blood clotting enzyme factor VIIa. The invention also relates to processes for the preparation of the compounds of formula I, to methods of inhibiting factor VIIa activity and of inhibiting blood clotting, to the use of the compounds of formula I in the treatment and prophylaxis of diseases which can be cured or prevented by the inhibition of factor VIIa activity such as thromboembolic diseases including thrombosis, restenosis, infarction, and angina, and the use of the compounds of formula I in the preparation of medicaments to be applied in such diseases. The invention further relates to compositions containing a compound of formula I in a mixture or otherwise in association with an inert carrier, in particular pharmaceutical compositions containing a compound of formula I together with pharmaceutically acceptable carrier substances or excipients and/or auxiliary substances or additives.